Based on progress made in this program of research in developing new selenium compounds that have chemopreventive activity and that are well- tolerated, and on the identification in our project of biomarkers of chemopreventive and toxic activities of selenium compounds, the following aims are proposed. AIM 1. IDENTIFY STRUCTURE-ACTIVITY RELATIONSHIPS THAT DIRECT BOTH COMPOUND DEVELOPMENT AND MECHANISTIC INVESTIGATIONS. We will evaluate the potential chemopreventive efficacy of newly synthesized selenium compounds (Block and Ganther projects) in an in vitro system. This system was designed to eliminate from consideration those compounds that induce necrosis or sublethal DNA damage, and to rank those compounds without such activities based on their ability to reduce cell accumulation. Newly synthesized selenium compounds will be prioritized for in vivo evaluation for chemopreventive activity based on these data (lp project). AIM 2. DETERMINE THE EFFECTS OF DIFFERENT TYPES OF SELENIUM COMPOUND ON THE EXPRESSION OF GENES INVOLVED IN CONTROLLING CELL NUMBER HOMEOSTASIS. One of the central hypotheses of the previous grant application was that selenium was affecting negative growth control mediated by the induction of apoptosis. We have now published evidence that not only confirms this, but that also implies that different types of selenium induce apoptosis by different mechanisms. In this specific aim we will test this hypothesis by studying the effect of different types of selenium on the expression of genes recognized to be involved in growth arrest and cell death pathways. AIM 3. DETERMINE IF THE PROCESS OF CLONAL EXPANSION AND SELECTION IS AFFECTED BY SELENIUM. Our approach has two components. First, we will determine if a selenium compound affects the number and type of early neoplastic lesions induced by MNU using a newly developed model system in which the occurrence of ductal hyperplasias, atypical ductal hyperplasias, ductal carcinoma in situ and invasive carcinomas can be detected and quantified in the rat. Second, within these lesions the effects of selenium on the processes of cell proliferation and cell death by apoptosis will be quantified. Our goal is to determine how the pathogenetic pathway of mammary carcinogenesis is affected in order to identify gene specific mechanisms of cancer chemoprevention. The program of research of which this project is a component is highly integrated. Collectively the work proposed has the potential of identifying selenium compounds that target one or more specific gene- mediated events that lead to cancer. As a result this work is likely to identify effective, well tolerated selenium chemopreventive compounds and to establish their mechanism.